Dopamine beta-hydroxylase and its genetic variants in human health and disease.

Dopamine beta-hydroxylase (DßH) is an essential neurotransmitter-synthesizing enzyme that catalyzes the formation of norepinephrine (NE) from dopamine and has been extensively studied since its discovery in the 1950s. NE serves as a neurotransmitter in both the central and peripheral nervous systems and is the precursor to epinephrine synthesis in the brain and adrenal medulla. Alterations in noradrenergic signaling have been linked to both central nervous system and peripheral pathologies. DßH protein, which is found in circulation, can, therefore, be evaluated as a marker of norepinephrine function in a plethora of different disorders and diseases. In many of these diseases, DßH protein availability and activity are believed to contribute to disease presentation or select symptomology and are believed to be under strong genetic control. Alteration in the DßH protein by genetic polymorphisms may result in DßH becoming rate-limiting and directly contributing to lower NE and epinephrine levels and disease. With the completion of the human genome project and the advent of next-generation sequencing, new insights have been gained into the existence of naturally occurring DßH sequencing variants (genetic polymorphisms) in disease. Also, biophysical tools coupled with genetic sequences are illuminating structure-function relationships within the enzyme. In this review, we discuss the role of genetic variants in DßH and its role in health and disease.

A single nucleotide polymorphism in dopamine beta hydroxylase (rs6271(C>T)) is over-represented in inflammatory bowel disease patients and reduces circulating enzyme.

Inflammatory bowel diseases (IBD) are associated with altered neuronal regulation of the gastrointestinal (GI) tract and release of norepinephrine (NE). As sympathetic innervation of the GI tract modulates motility, blood flow, and immune function, changes in NE signaling may alter the risk of developing IBD. Dopamine beta-hydroxylase (DßH), the enzyme responsible for NE production, has been suggested to play a critical role in IBD, however the exact mechanism is unknown. We hypothesized that genetic variants of DßH could increase the risk of IBD. We performed genetic analysis on 45 IBD patients and 74 controls. IBD patients were screened by targeted exome sequencing and compared with NeuroX DßH single nucleotide polymorphism (SNP) genotyping data of the controls. Serum DßH protein levels for 15 IBD patients and 13 controls were evaluated using immunoblots and competitive ELISA. Seven SNPs were observed from DßH targeted exome sequencing in the 45 IBD patients. A single non-synonymous SNP, rs6271 (Arg549Cys), had a significant association with IBD patients; the odds ratio was a 5.6 times higher SNP frequency in IBD patients compared to controls (p = 0.002). We also examined the function and availability of the protein in both the IBD and control patients' sera bearing DßH Arg549Cys. Both control and IBD subjects bearing the heterozygote allele had statistically lower DßH protein levels while the intrinsic enzyme activity was higher. This is the first report of a noradrenergic genetic polymorphism (rs6271; Arg549Cys) associated with IBD. This polymorphism is associated with significantly lower levels of circulating DßH.

Homozygosity for the SCN10A Polymorphism rs6795970 Is Associated With Hypoalgesic Inflammatory Bowel Disease Phenotype.

Background: Hypoalgesic inflammatory bowel disease (IBD), a condition in which patients with active disease do not perceive and/or report abdominal pain, is associated with serious complications and there is a lack of cost-effective, reliable diagnostic methods to identify "at-risk" patients. The voltage-gated sodium channels (VGSC's), Nav1.7, Nav1.8, and Nav1.9, are preferentially expressed on nociceptive neurons, and have been implicated in visceral inflammatory pain. At least 29 VGSC single nucleotide polymorphisms (SNPs) have been implicated in chronic somatic pain syndromes, but little is known about their role in human visceral sensation. We hypothesized that disruptive VGSC polymorphisms result in anti-nociceptive behavior in IBD. Methods and Findings: We performed targeted exome sequencing and/or TaqMan genotyping to evaluate the Nav1.7, Nav1.8, and Nav1.9 genes (SCN9A, SCN10A and SCN11A) in 121 IBD patients (including 41 "hypoalgesic" IBD patients) and 86 healthy controls. Allelic and genotypic frequencies of polymorphisms were compared among study groups who had undergone characterization of intestinal inflammatory status and abdominal pain experience. Forty-nine total exonic SNPs were identified. The allelic frequency of only one non-synonymous SNP (rs6795970 [SCN10A]) approached significance in hypoalgesic IBD patients when compared to other IBD patients (p = 0.096, Fisher's exact test). Hypoalgesic IBD patients were more likely to be homozygous for this polymorphism (46 vs. 22%, p = 0.01, Fisher's exact test). Conclusions: This is the first human study to demonstrate a link between a genetic variant of SCN10A and abdominal pain perception in IBD. These findings provide key insights into visceral nociceptive physiology and new diagnostic and therapeutic targets to consider in IBD and other gastrointestinal conditions associated with chronic abdominal pain. Further studies are required to elucidate the precise pathophysiological impact of the rs6795970 polymorphism on human gastrointestinal nociception.

Effect of reduction treatment on copper modified activated carbons on NO(x) adsorption at room temperature.

Activated carbon was impregnated with copper salt and then exposed to reductive environment using hydrazine hydrate or heat treatment under nitrogen at 925 °C. On the obtained samples, adsorption of NO(2) was carried out at dynamic conditions at ambient temperature. The adsorbents before and after exposure to nitrogen dioxide were characterized by X-ray diffraction (XRD), thermal analysis, scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM-EDX), X-ray photoelectron spectroscopy (XPS), N(2)-sorption at -196 °C, and potentiometric titration. Copper loading improved the adsorption capacity of NO(2) as well as the retention of NO formed in the process of NO(2) reduction on the carbon surface. That improvement is linked to the presence of copper metal and its high dispersion on the surface. Even though both reduction methods lead to the reduction of copper, different reactions with the carbon surface take place. Heat treatment results in a significant percentage of metallic copper and a reduction of oxygen functional groups of the carbon matrix, whereas hydrazine, besides reduction of copper, leads to an incorporation of nitrogen. The results suggest that NO(2) mainly is converted to copper nitrates although the possibility to its reduction to N(2) is not ruled out. A high capacity on hydrazine treated samples is linked to the high dispersion of metallic copper on the surface of this carbon.